Confirming the diagnosis of growth hormone deficiency (GHD) and transitioning the care of patients with childhood-onset GHD

Growth hormone deficiency (GHD) diagnosed in childhood may persist into adult life. After attainment of final height, retesting of the patient's growth hormone-insulin-like growth factor (GH-IGF) axis using the adult GHD diagnostic criteria should be performed after an appropriate interval of 1-3 months off GH therapy. At the time of retesting, other pituitary hormones and serum IGF-I levels should also be measured. The opportunity should be taken to assess body composition, bone mineral density, and fasting lipid and insulin levels. Patients with severe, long-standing, multiple pituitary hormone deficiency, genetic defects, or severe organic GHD can be excluded from GH retesting. When the diagnosis of adult GHD is established, continuation of GH therapy can be recommended unless there is a known risk of diabetes mellitus or malignancy. The patient's transition to GH replacement in adulthood should be arranged as a close collaboration between the pediatric and adult endocrinologists, who should discuss the reinitiation of treatment with the patient.     

Growth hormone treatment in Noonan syndrome

Growth responses to growth hormone (GH) treatment in Noonan syndrome are compared with those in short children with the other growth disorders. The responses in Noonan syndrome are much less than those in children with GH deficiency, a little less than those in children with non-endocrine short stature and almost the same as those in children with Turner syndrome. As it is speculated that GH induces puberty earlier that expected in Noonan Syndrome, the efficiency of GH treatment for final height in Noonan syndrome is not promising.     

Growth Response in the First Year of Growth Hormone Treatment in Prepubertal Children with Organic Growth Hormone Deficiency: a Comparison with Idiopathic Growth Hormone Deficiency

ABSTRACT. Patients in the Kabi International Growth Study (KIGS) up to 1st January 1990 who had organic growth hormone deficiency (OGHD) were identified. They accounted for 21% of all patients with growth hormone deficiency (GHD). Diagnostic categories within the OGHD group included septo-optic dysplasia, postnatal trauma, craniopharyngioma, other cranial tumours, and following acute leukaemia. Features at presentation and during the first year of hGH treatment were compared with those of children with idiopathic growth hormone deficiency (IGHD). Ninety prepubertal children with OGHD were selected for comparison of observed first-year height velocity (HV) with predicted values based on those observed in 257 children with IGHD. Those with septo-optic dysplasia, postnatal trauma and craniopharyngioma responded as predicted, whereas those with other cranial tumours appeared to grow less well than predicted. Glucocorticoid treatment did not affect response, but previous cranial or craniospinal irradiation was found to be associated with an observed HV which was significantly less than predicted.     

Autoimmune polyglandular syndrome Type 3 and growth hormone deficiency

Quintos JB, Grover M, Boney CM, Salas M. Autoimmune polyglandular syndrome type 3 and growth hormone deficiency. The simultaneous occurrence of prepubertal Graves' disease, type 1 Diabetes Mellitus (DM), and Growth hormone deficiency (GHD) is uncommon. GHD has been reported in Autoimmune Polyglandular Syndrome (APS) Type 1 and Type 2 but not in APS Type 3. We report a 3‐yr‐old boy who presented simultaneously with type 1 DM and Graves' disease. After he developed urticarial rash to Propylthiouracil and Methimazole with persistent thyrotoxicosis, he received 8 millicuries of ¹³¹I at 5 yr of age. We diagnosed GHD at age 8 yr 8 months because of growth deceleration (from 95 to 25%) and abnormal growth rate (3 cm/yr) despite euthyroidism, fair glycemic control, and normal weight gain. Both insulin‐like growth factor (IGF) 1 (90 ng/mL; normal 113–261 ng/mL) and IGFBP3 (1.3 mcg/mL; normal 2.1–4.2 mcg/mL) levels were low and peak growth hormone level measured by RIA was 5.2 ng/mL after L‐Dopa and insulin tolerance test. The rest of his pituitary functions and magnetic resonance imaging of the pituitary gland were normal. Growth hormone treatment (0.3 mg/kg/wk) was administered at 8 yr 9 months until near final adult height (FAH). Near FAH (172 cm) was close to midparental target height of 180 cm. GHD may be a component of all APS even though it is rare. Growth in treated children with Graves' disease should be followed closely as catch down growth below genetic height potential may be a harbinger of underlying GHD.     

Growth in a case of Russell-Silver syndrome treated for hypopituitarism

The growth characteristics of Russell-Silver syndrome (RSS) include dwarfism of prenatal onset, moderate retardation of bone age and normal postnatal height velocity. We describe a case of hypopituitarism in a girl with typical RSS who suffered from a severe trauma at birth. Signs of hypopituitarism appeared during childhood. Before substitutive treatment, a short course of human growth hormone (hGH) induced a moderate rise in plasma IGF-I levels which was within the range observed in other pituitary dwarfs. Under replacement therapy, catch-up growth was similar to what is observed in other growth hormone deficient children. However, bone age matured much faster than chronological age. This observation appears to be a particular feature of RSS, possibly enhanced by hGH therapy. An improvement of adult height beyond the final height usually observed in RSS children without endocrine disturbances should therefore not be expected from hGH therapy. Growth hormone deficiency and RSS do not appear to be causally related. However, in each child with RSS, a particular attention should be given to a decreased height velocity, a severely delayed bone age as well as a history of major perinatal problems. Should one of these factors be found, a careful evaluation of the hypothalamo-pituitary axis ought to be performed with, accordingly, an appropriate substitutive therapy.     

Growth in disorders of adrenal hyperfunction

This article reviews how growth is affected in disorders of adrenal hyperfunction. Growth is disturbed by adrenal hypersecretion of androgens or cortisol. Adrenal androgens, when in excess, lead to advanced linear growth and skeletal maturation, and prolonged hypercortisolemia leads to the suppression of growth hormone (GH) secretion and inhibition of somatomedin C and other growth factor effects on their target tissues. In virilizing adrenal tumors height is increased at diagnosis, but after surgical cure the final height is usually in the normal range. In congenital adrenal hyperplasia height is usually compromised by advanced skeletal maturation or by suppressed growth, particularly in the first years of life, due to excess glucocorticoid treatment. The final height is reduced in both clinical forms (salt wasting and simple virilizing) and sexes in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Growth impairment is also the hallmark of Cushing syndrome of whatever etiology when it occurs in children and growing adolescents, and the final height of these patients, even after surgical cure, remains compromised. This is apparently due to direct or indirect growth impairment by the hypercortisolism during the disease, followed by inadequate catch-up growth. Although it seems that GH treatment might be beneficial for improving final height both in patients with congenital adrenal hyperplasia who have poor height predictions and in patients with Cushing disease and GH deficiency, a larger number of studies is needed to confirm this suggestion.     

Pituitary function assessment in short stature by a combined hormonal-stimulation test

We utilized a combined, hormonal-stimulation test (CHST) using sequentially-administered insulin, thyrotropin-releasing hormone, gonadotropin-releasing hormone, and levodopa to assess 51 children with short stature and/or pathologic growth. Growth hormone, thyrotropin, gonadotropins, cortisol, and prolactin levels were sampled over two hours. All patients with appropriate predicted adult heights, delayed bone ages, and normal growth velocities of 4.0 cm/y or greater demonstrated normal pituitary responses. Two of 12 patients with predicted heights 2.5 SDs lower than target height and normal growth velocity demonstrated isolated growth hormone deficiency. Nine of 11 patients had a pathologic growth hormone deficiency or panhypopituitarism. Evaluation of pituitary function by combined sequential hormonal stimulation is fruitful in children with pathologic growth patterns but not in children with normal growth velocities and normal predicted adult height.     

Diagnostic limitations of spontaneous growth hormone measurements in normally growing prepubertal children

To evaluate whether the measurement of the spontaneous overnight growth hormone secretion in prepubertal children clearly separated normal children from subjects with growth hormone deficiency, we studied 45 prepubertal normally growing children (10 with normal height and 35 with constitutional growth delay) and compared their overnight growth hormone secretion with that of a group of subjects with either isolated growth hormone deficiency or neurosecretory dysfunction. Peak growth hormone levels (greater than or equal to 10 ng/mL) following oral clonidine administration were normal in individuals with normal height, constitutional growth delay, and neurosecretory dysfunction, as was the basal somatomedin C concentration; subjects with growth hormone deficiency had low peak growth hormone levels (less than 10 ng/mL) following oral clonidine administration as well as low basal somatomedin C values. The mean 9-hour overnight growth hormone concentration, total growth hormone output, total number of nocturnal pulses, and the mean peak growth hormone response during nocturnal sampling were similar in the normal height and constitutional growth delay groups and significantly greater than those seen in subjects with either growth hormone deficiency or neurosecretory dysfunction. Twelve (26.6%) of 45 normally growing children (4 to 10 normal height and 8 of 35 constitutional growth delay), however, had low overnight growth hormone levels (less than 3 ng/mL), which overlapped results obtained in the growth hormone-deficient or neurosecretory dysfunction groups. Frequent overnight growth hormone (GH) sampling does not always separate normal-growing children from those with partial or complete GH deficiency. In our this study over one quarter of the normally growing children had overnight GH levels in the range of children with either GH deficiency or neurosecretory dysfunction. These findings, in addition to the cost and difficulty in performing this test, do not support the measurement of spontaneous GH as a routine test in short but normally growing prepubertal children.     

Parental Heights of Children with Idiopathic Growth Hormone Deficiency: Analysis from the Kabi International Growth Study

International Board, Kabi International Growth Study (Kabi, Stockholm, Sweden). Parental heights of children with idiopathic growth hormone deficiency: analysis from the Kabi International Growth Study. Acta Paediatr Scand [Suppl] 356: 178, 1989.
In an international study of children treated with growth hormone (GH), parental heights of 554 children with idiopathic growth hormone deficiency (IGHD) and of 248 children with secondary or'organic'growth hormone deficiency (OGHD) were ascertained. The maternal height SDS of IGHD children was -0.41 ± 1.26 (mean ± SD) and the maternal height SDS of OGHD children was 0.03 ± 1.11 ( p < 0.006). Paternal height SDS of IGHD children was -0.19 ± 1.08, and paternal height SDS of OGHD children was 0.15 ± 1.08 ( p < 0.006). Adverse deliveries were associated with significantly shorter mothers ( p = 0.04) and a greater discrepancy between paternal and maternal heights ( p < 0.006).     

Growth and puberty after growth hormone treatment after irradiation for brain tumours

The impact of treatment with either cranial or craniospinal irradiation with or without cytotoxic chemotherapy for a brain tumour distant from the hypothalamic-pituitary axis was assessed in 29 children who had reached final height. All had received growth hormone treatment for radiation induced growth hormone deficiency. Final height, segmental growth during puberty, and duration of puberty were studied. Both craniospinal irradiation and the use of chemotherapy resulted in a significant and equal reduction in final height; this effect in those children who received both craniospinal irradiation and chemotherapy was additive. The degree of height loss was related to the age at irradiation, the most profound effect on final height occurring in the youngest at irradiation. The mean duration of puberty from G2-G4/B2-B4 (1.97 years) was not significantly different from the duration of puberty in normal children. Growth hormone increases growth velocity in children with radiation induced growth hormone deficiency but their final height is significantly less than their mid-parental height. The use of spinal irradiation and chemotherapy in the original treatment of brain tumours has a marked effect on growth which is not overcome with the use of growth hormone treatment in current doses. Early puberty of normal duration contributes to poor growth.     

Growth and puberty after growth hormone treatment after irradiation for brain tumours.

The impact of treatment with either cranial or craniospinal irradiation with or without cytotoxic chemotherapy for a brain tumour distant from the hypothalamic-pituitary axis was assessed in 29 children who had reached final height. All had received growth hormone treatment for radiation induced growth hormone deficiency. Final height, segmental growth during puberty, and duration of puberty were studied. Both craniospinal irradiation and the use of chemotherapy resulted in a significant and equal reduction in final height; this effect in those children who received both craniospinal irradiation and chemotherapy was additive. The degree of height loss was related to the age at irradiation, the most profound effect on final height occurring in the youngest at irradiation. The mean duration of puberty from G2-G4/B2-B4 (1.97 years) was not significantly different from the duration of puberty in normal children. Growth hormone increases growth velocity in children with radiation induced growth hormone deficiency but their final height is significantly less than their mid-parental height. The use of spinal irradiation and chemotherapy in the original treatment of brain tumours has a marked effect on growth which is not overcome with the use of growth hormone treatment in current doses. Early puberty of normal duration contributes to poor growth.     

Serum zinc, insulin-like growth factor-I and insulin-like growth factor binding protein-3 levels in children with type 1 diabetes mellitus

BACKGROUND: Growth is impaired during the course of diabetes mellitus (DM). Derangement of the growth hormone/insulin-like growth factor (IGF) axis, insulinopenia and zinc deficiency are the possible causative factors of this impairment. Zn supplementation is proven to attenuate hyperglycemia in mice but its use to ameliorate impaired height is still a matter of discussion. OBJECTIVE: To investigate serum Zn, IGF-I and IGF binding protein-3 (IGFBP-3) levels and to emphasize the potential beneficial effects of Zn supplementation for the prevention of growth failure in children with type 1 DM (DM1). Patients and Methods: Twenty-eight patients with DM1 and 15 control children were included in the study. Zn levels were measured by flame atomic absorption spectrophotometry; IGF-I and IGFBP-3 levels were measured by immunoradiometric assay. RESULTS: Mean serum Zn levels were significantly lower in diabetic children taken as a whole and as their pubertal subgroup compared to the controls. Mean serum IGF-I and IGFBP-3 levels were significantly lower in both prepubertal and pubertal diabetic groups compared to those of control groups. CONCLUSION: From the results of our study, it can be hypothesized that serum Zn levels should be closely monitored during the course of DM1 and supplementation may be given to patients, especially at the time of puberty. This hypothesis needs to be confirmed by further studies.     

Once versus twice daily injections of growth hormone in children with idiopathic short stature

The aim of this study was to compare the growth response of 22 short pre-pubertal children without growth hormone deficiency, treated with a single daily growth hormone injection (group A), to the growth response of 27 similar children, treated with the same daily dose divided into 2 subcutaneous injections per day (group B), for 1 y, in a randomized study. GH treatment significantly promoted growth parameters, height standard deviation score and height velocity standard deviation score in both groups. Serum insulin-like growth factor I was also increased. There were no significant differences in growth response, serum IGF-I levels, or the advance in bone age between the two study groups after 1 y of GH therapy. We conclude that twice daily s.c. growth hormone injections provide no advantages over once daily injection of the same dose in promoting the linear growth of short children without growth hormone deficiency.     

Clinical Usefulness of Urinary Growth Hormone Measurement in Short Children

Growth hormone GH) levels in nocturnal urine were measured in 96 short children and 73 children of normal height in order to investigate whether urinary CH levels reflect spontaneous GH secretion and whether they might be used to screen short children for GH treatment. GH levels in 24-hour urine samples were significantly correlated with urinary albumin and β₂-microglobulin levels in normal children, demonstrating an influence of renal function on urinary GH measurements. Nocturnal urinary GH levels showed significant positive correlations with mean serum GH levels during 3 hours of sleep ( r = 0.26. p < 0.05) and plasma insulin-like growth factor 1 (IGF-I) levels, reflecting physiological GH secretion. Urinary GH levels were significantly lower in the eight children with complete GH deficiency (3.1 ± 2.3 ng/g creatinine) than in the normal children (13.8 ± 11.2 ng/g creatinine). Urinary GH levels in three other groups of short children, partial CH deficiency (11.1 ± 16.9 ng/g creatinine), impaired GH secretion during sleep (10.4 ± 12.6 ng/g creatinine) and non-endocrine short stature (18.8 ± 19.5 ng/g creatinine), were not significantly different from those in the normal children. However, when the cut-off point for defining GH insufficiency was set at 5 ng/g creatinine, 87.5% (21 out of 24) of the short children with low urinary GH levels were suitable subjects for GH treatment (i.e. had complete GH deficiency, partial GH deficiency or impaired GH secretion during sleep). It is concluded that urinary GH measurement, though influenced by renal function, is potentially a simple, non-invasive and clinically useful method for screening short children for GH insufficiency. Further refinements of the technique are required before it can be widely applied.     

胰岛素样生长因子-1受体基因与特发性矮小相关性研究进展

生长激素-胰岛素样生长因子(GH-IGF)轴是调节儿童生长发育中最重要的神经内分泌轴.胰岛素样生长因子-1受体( IGF-1 R)是调节该轴的激素受体级联反应的效应分子,它的分子结构或功能异常,将影响靶基因IGF-1与其结合,从而引起生长障碍,可能与特发性矮小(ISS)发生有一定关系.国内外尚无IGF-1R基因与ISS的研究,为探讨其与ISS的关系,现就近年来有关IGF-1 R与人体生长障碍的研究作简要综述.     

Diagnostic means to exclude deficient secretion of growth hormone in paediatric practice (author's transl)

Growth hormone serum levels were measured radioimmunologically in 365 children with stunted growth before and after 10 minutes of stair-climbing, and in 134 children before and after 10 minutes of physical stress produced by means of a bicycle ergometer. Only 20% of the children had a growth hormone level of more than 5 ng/ml before initiation of the study. After climbing the stairs, the hormone level rose in 160 children to more than 5 ng/ml (max. 41.1 ng/ml). Growth hormone deficiency could thus be definitively eliminated as the cause of retarded growth in only 46% of the patients. In 16 (of 22) children of normal size, in 34 (of 49) chilkren with arrested growth who had a corresponding familial background, and in 33 (of 57) children with constitutionally conditioned retarded development, the growth hormone content after exercise on an rose to more than 5 ng/ml. Hence, a total of 65% of the children showed a satisfactory increase of the growth hormone. It follows from this that the ergometer exercise test is more suitable that the stair-climbing test to exclude hormone deficiency as the cause of stunted growth, and can, therefore, be recommended for use in paediatric practice as a supplementary examination method besides clinical findings, case history and determination of the growth rate.     

When are we diagnosing growth hormone deficiency?

The height and age at presentation of 458 children beginning treatment with growth hormone between January 1980 and June 1984 were retrospectively analysed. Three hundred and nine children with isolated growth hormone deficiency had a mean (SD) age of 10 (4.1) years on beginning treatment and a mean (SD) height standard deviation score (SDS) of -3.73 (0.93). One hundred and nine patients with hypothalamopituitary tumours began treatment with growth hormone on average 3.3 years after diagnosis of the tumour and at a mean (SD) height SDS of -2.42 (1.49). In both of these categories the height SDS showed a considerable improvement compared with previous reports. Forty two patients with growth hormone deficiency secondary to cranial irradiation started treatment with growth hormone on average 6.1 years after treatment for their tumours and had a height SDS of -2.45 (1.02) compared with that of -2.45 (0.98) seen in nine similar patients from the United Kingdom starting treatment with growth hormone between 1975 and 1978. Although closer surveillance of short children in the community is leading to earlier diagnosis of growth hormone deficiency, this could possibly be diagnosed earlier if routine screening of height was to be carried out at school entry. In addition, patients who have received cranial irradiation should be regularly measured and investigated when their height velocity becomes subnormal.     

Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity

Burren CP, Wanek D, Mohan S, Cohen P, Guevara-Aguirre J, Rosenfeld RG. Serum levels of insulin-like growth factor binding proteins in Ecuadorean children with growth hormone insensitivity. Acta Pædiatr 1999; Suppl 428: 185–91. Stockholm. ISSN 0803–5326
Although insulin-like growth factor binding proteins (IGFBPs) are known to be important modulators of the action of insulin-like growth factors (IGFs), regulation of their production in vivo is not completely understood. Serum concentrations of IGFBP-3, -4 and -5 and acid-labile subunit (ALS) were therefore examined in 20 children with growth hormone (GH) insensitivity before and after 6 months of therapy with recombinant human IGF-I (80 or 120 ug/kg twice daily). The IGFBP concentrations in these children were compared with those in 62 GH-deficient children receiving GH therapy for 3 months. Serum levels of IGFBP-3, -4 and -5 and ALS all increased significantly ( p < 0.0001) in GH-deficient children in response to GH therapy, whereas no significant increases occurred in the children with GH insensitivity. These findings indicate that GH is responsible for the regulation of serum levels of IGFBP-3, -4 and -5 and ALS, and that IGF-I does not directly regulate the concentrations of these circulating IGFBPs. □ Growth hormone, growth hormone insensitivity, insulin-like growth factor I, insulin-like growth factor binding protein     

Growth hormone treatment in young children with Down's syndrome: effects on growth and psychomotor development.

BACKGROUND: Learning disability and short stature are cardinal signs of Down's syndrome. Insulin-like growth factor I (IGF-I), regulated by growth hormone (GH) from about 6 months of age, may be involved in brain development. AIMS: To study long term effects of GH on linear growth and psychomotor development in young children with Down's syndrome. Study design-Fifteen children with Down's syndrome were treated with GH for three years from the age of 6 to 9 months (mean, 7.4). Linear growth, psychomotor development, skeletal maturation, serum concentrations of IGF-I and its binding proteins (BPs), and cerebrospinal fluid (CSF) concentrations of IGF-II were studied. RESULTS: The mean height of the study group increased from -1.8 to -0.8 SDS (Swedish standard) during treatment, whereas that of a Down's syndrome control group fell from -1.7 to -2.2 SDS. Growth velocity declined after treatment stopped. Head growth did not accelerate during treatment. No significant difference in mental or gross motor development was found. The low concentrations of serum IGF-I and IGFBP-3 became normal during GH treatment. CONCLUSIONS: GH treatment results in normal growth velocity in Down's syndrome but does not affect head circumference or mental or gross motor development. Growth velocity declines after treatment stops.     

Growth promotion by oxandrolone in a girl with short stature and early pubertal development treated with growth hormone and gonadotropin-releasing hormone-analogue. A case study

Gonadotropin-releasing hormone (GnRH)-analogues are widely used for treating precocious puberty, and occasionally in short patients and patients with growth-hormone deficiency, in order to delay pubertal development and increase final height. Yet, many of these children only decelerate growth velocity and neither improve in final height nor even in height prediction. As GnRH-analogue treatment dramatically reduces sexual steroid levels, I hypothesized the need for steroid hormone substitution during this treatment. Growth promotion was tried in a healthy girl, with a very unsatisfying height prediction of only 144 cm, using a combination of GnRH-analogue (75 /μg/kg/4 weeks), plus growth hormone (4 IU/m